Pellet-type formulation intended for treating the intestinal tract

ABSTRACT

An orally adminsterable pharmaceutical pellet formulation for the treatment of the intestinal tract is disclosed, which comprises a core and an enteric coating, the core including, as a pharmaceutical active compound, aminosalicyclic acid or a pharmaceutically tolerable salt or a derivative thereof.

The present invention relates to a pellet formulation for the treatmentof the intestinal tract, which comprises, as a pharmaceutical activecompound, aminosalicylic acid or a pharmaceutically tolerable salt orderivatives thereof.

The active compound aminosalicylic acid (in particular 5-ASA) or itsderivatives have been used successfully for a relatively long time forthe treatment of intestinal disorders, such as, for example, ulcerativecolitis and Crohn's disease (DE 31 51 196 A1).

The use of 5-ASA and its derivatives as a chemotherapeutic agent incolonic cancer is likewise known, polyps in the colon and rectum beingassociated with an increased risk of carcinoma (WO 95/18622).

A coloscopic polypectomy in patients with polyps in the colon and/orrectum results in a considerable reduction in risk of the formation ofcolonic carcinomas and is recommended as a therapy, in particular in thecase of colorectal polyps. The reccurrence rate after polypectomy,however, is high and amounts to about 6-30% per year. Aminosalicylicacid is suitable for the longer-term treatment of such patients andlowers the reccurrence rate of colorectal polyps.

The action of aminosalicylic acid in the treatment of intestinaldisorders, or in the prevention of their recurrence or in the preventionof secondary disorders arising therefrom and possible accompanyingdisorders takes place by means of the contact of the active compounddirectly at the site of the disorder in the intestine, the action of theaminosalicylic acid, or a derivative thereof, being directly related toits local concentration in the intestinal area to be treated.

Since inflammatory processes often affect relatively large sections ofthe intestinal tract, the pharmaceutical form should spread reproduciblyover wide areas of the intestine and release the active compound only atthe site of inflammation.

A problem in the treatment with aminosalicylic acid is that the activecompound is very easily absorbed and can be excreted via the kidneybefore its action can occur.

In the prior art, tablets and pellets are known which are coated with anenteric coating in order to thus prevent a premature release of theactive compounds.

FR-A2 692 484 discloses a tablet for the controlled release of 4-ASA ina hydrophllic matrix which consists of swellable polymers forming a gelbarrier, and having an enteric coating. After dissolution of thecoating, the matrix swells and forms a gel barrier through which theactive compound diffuses out. After an approximately two-hour lag phase,the composition disclosed in FR-A 2 692 484 releases the active compoundapproximately linearly in the intestine over a period of time of afurther 14 h.

EP 0 453 001 A1 discloses a pharmaceutical composition in which theactive compound is covered with at least two membranes, of which one issoluble at a pH of ≧5.5 and the other is insoluble at this pH but ispermeable to the intestinal fluids.

EP 0 148 811 A1 discloses a pharmaceutical composition which consists ofa core which contains the active compound. The core is surrounded by twolayers, of which the inner layer is a diffusion membrane and the secondlayer is an anionic polymer and/or a fatty acid having a pK_(a) of 4.5to 7.

EP 0 629 398 A1 discloses pharmaceutical compositions in which theactive compound-containing core is surrounded by an enteric phase.According to Example 2, the core can contain small amounts ofhydroxypropyl-cellulose. The active compound should be released rapidlyafter dissolution of the enteric phase.

EP 0 485 840 A2 discloses an oral pharmaceutical form which contains ashell material surrounding the active compound consisting of apolysaccharide and a film-forming polymer material.

A disadvantage in the case of the pharmaceutical formulations known inthe prior art is that the active compound is also absorbed into theblood circulation. This amount of active compound is thus lacking in theintestine, so that the effective dose of the medicament is reduced bythe part of the active compound which is found in the blood.

Moreover, patients who suffer from intestinal disorders frequently haveto be further treated over relatively long periods with the activecompound, or derivatives thereof, after the acute disorder has died downin order to prevent the disorder flaring up again or secondary disordersresulting from the original disorder. In the case of such a long-termtreatment, however, it has proven to be a problem that a certainnephrotoxicity of systemically available 5-ASA, i.e. 5-ASA found in thebloodstream, or derivatives thereof cannot be excluded (M. Barry,Prescribers Journal, 1992, 32, 205).

It is thus an object of the present invention to make available anorally administrable pharmaceutical formulation which does not havethese disadvantages. According to the invention, formulations aretherefore made available which have a controlled release profile whichresults in a high local active compound concentration at the site ofaction and simultaneously guarantees a blood level of the activecompound which is as low as possible.

In the context of the present invention, it has now been found thatpellet formulations are particularly suitable for this purpose, sinceunlike a tablet they spread the pharmaceutical form reproducibly overwide areas of the intestine and are thus particularly suitable fortreatment of inflammatory processes, which often affect relatively largesections of the intestinal tract. In order to achieve the necessarylocal active compound concentration, the active compound must in thiscase be released at the site of inflammation within a relatively shorttime (up to a few hours) without, however, it being released virtuallyimmediately, in order that its action does not wear off too rapidly.

The use of a swellable, gel-forming matrix such as described in FR-A 2692 484 is not suitable for pellets having a diameter of ≦3 mm, since onaccount of the small diameter the polymer is very rapidly penetrated bythe water, eroded as a result, and the active compound would thus bereleased virtually immediately (about 30 min).

In the context of the present invention, however, it has surprisinglybeen found that, if the active compound is present in the pellet core ina non gel-forming polymer matrix which is essentially insoluble andpermeable to intestinal fluids and the active compound, a markedlyreduced release of the active compound into the blood, withsimultaneously increased local concentration of the active compound atthe site of the disorder in the intestine, is guaranteed in comparisonwith aminosalicylic acid formulations already known in the prior art.

The present invention thus relates to an orally administrablepharmaceutical pellet formulation having a controlled release profilefor the treatment of the intestinal tract, which comprises a core and anenteric coating, and, if appropriate, further pharmaceutically tolerableadditives, the core including as a pharmaceutically active compoundaminosalicylic acid or a pharmaceutically tolerable salt or derivativethereof, wherein the active compound is present in the core in a nongel-forming polymer matrix which is essentially insoluble in theintestinal tract and permeable to intestinal fluids and the activecompound, the matrix-forming polymer making up at least 1% by weight ofthe total weight of the core.

The invention furthermore relates to a process for the production of thepellets described above and their use for the production of a medicamentfor the treatment of intestinal disorders, such as inflammatoryintestinal disorders, preferably in the active phase and/or in theremission phase, for the prevention of these disorders, for theprevention of the recurrrence of these disorders or secondary disordersresulting therefrom, and of possible accompanying disorders and also forthe treatment of intestinal cancer. The medicament is particularlysuitable for the treatment of inflammatory intestinal disorders such asCrohn's disease and ulcerative colitis, and for the prevention,treatment and/or prevention of the reformation of polyps in thegastrointestinal tract. Moreover, the medicament is suitable for theprevention of colorectal carcinomas in patients with adenomas and/orpolypous growth, in particular with polypous growth in the intestine.The medicament is moreover used for lowering the recurrence rate ofcolorectal polyps.

Preferred active compounds are 5-aminosalicylic acid (also calledmesalazine), 4-aminosalicylic acid and, serving as a prodrug for 5-ASA,2-hydroxy-5-phenylazobenzoic acid derivatives such as sulfasalazine(5-[4-(2-pyridylsulfamoyl)phenylazo]salicylic acid) and balsalazide (thesodium salt of the azo derivative of 4-aminobenzoyl-β-alanine and5-aminosalicylic acid) 5-ASA is particularly preferred.

In addition to the active compound, the pellet core comprises 1% byweight, based on the total weight of the core, of a matrix-forming, nongel-forming polymer which is essentially insoluble in the intestinaltract and permeable to intestinal fluids and the active compound.Suitable matrix-forming polymers are, for example, those polymers whichare known in the prior art as coating lacquers for delayed-releasepharmaceuticals, such as, for example, (meth)acrylic ester copolymers.

Among the polymers which are essentially insoluble in the intestinaltract and permeable to intestinal fluids and the active compound, thoseare preferred which are insoluble or particularly preferablywater-insoluble in the intestinal tract.

Methyl acrylate copolymers and ammoniomethacrylate copolymers of thetype such as can be obtained under the tradename Eudragit® RS/RL/NE areparticularly preferred. As functional groups, these polymers have estergroups (Eudragit® NE) or ammonium groups (Eudragit® RL/RS). Poly(ethylacrylate, methyl methacrylate) and poly(ethyl acrylate, methylmethacrylate, trimethylammonioethyl methacrylate chloride) arepreferred. These polymers are obtainable, for example, as poly(ethylacrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion asEudragit® NE 40 D and as poly(ethyl acrylate, methyl methacrylate,trimethylammonioethyl methacrylate chloride) 1:2:0.1 in 12.5% strengthisopropanolic solution as Eudragit® RS 12.5 and in the composition1:2:0.2 as Eudragit® RL 12.5. The most preferred is Eudragit® NE 40 D.

The polymer must be present in an amount which is sufficient to form amatrix for the active compound and which guarantees a delayed release ofthe active compound. For this purpose, an amount of at least 1% byweight, preferably at least 4% by weight, based on the total weight ofthe core, has proven suitable. Larger amounts of, for example,approximately 21% by weight can also be employed. 4% by weight to 10% byweight is preferably employed.

The active compound is preferably homogeneously dispersed in the matrixdescribed above and is released with a delay after dissolving theenteric coating. The matrix with the active compound homogeneouslydispersed therein advantageously extends through the entire core.

The enteric coating should only dissolve after the formulation has leftthe stomach. Necessary coatings for this purpose are disclosed in theprior art (e.g. EP 0 453 001 A1).

Preferred enteric coatings according to the invention comprise amethacrylic acid copolymer or methylhydroxypropylcellulose phthalate.Poly(methacrylic acid, methyl methacrylates), which are obtainable underthe tradenames Eudragit® L or S and have free carboxyl groups asfunctional groups, are preferred. These polymers are insoluble in thegastric juice, but dissolve in digestive juices above pH 5.5-7 dependingon the number of functional carboxyl groups. Poly(methacrylic acid,methyl methacrylate) 1:1 (Eudragit® L 100; methacrylic acid copolymer,USP/NF type A) and poly(methacrylic acid, methyl methacrylate) 1:2(Eudragit® S; methacrylic acid copolymer, USP/NF type B) areparticularly preferred. Eudragit® L 100 is the most preferred. Mixturesof the coating materials mentioned, in particular of Eudragit® L andEudragit® S, can also be used.

The pellet formulation can comprise one or more coatings, however pelletformulations in which the pellet only comprises one coating arepreferred.

Both the core and the coating of the pellet formulation according to theinvention can include one or more of the abovementioned matrix orcoating materials.

The pellet formulations according to the invention can additionallycontain further pharmaceutically tolerable additives both in the coreand in the coating. Examples of pharmaceutically tolerable additivesinclude polyvinylpyrrolidone, microcrystalline cellulose, silica,magnesium stearate, lactose, cornstarch, triethyl citrate, talc,titanium dioxide and polyethylene glycol.

A particularly preferred pellet formulation according to the presentinvention comprises 5-ASA as an active compound in the core in apoly(ethyl acrylate, methyl methacrylate) 2:1 matrix, the polymercontaining ester groups as functional groups, and an enteric coatingwhich contains poly(methacrylic acid, methyl methacrylate) 1:1 or 1:2with free carboxyl groups as functional groups, and, if appropriate,further pharmaceutically tolerable additives.

Moreover, a mixture of Eudragit® S and Eudragit® L, preferablyapproximately 1:1, is advantageously employed in a coating for thepellet formulations according to the invention.

The pellet formulation according to the invention is distinguished by acontrolled release profile. Preferably, the release of active compoundin 0.1 M HCl after 2 h is <10%, in particular <5%, and in artificialgastric juice at pH 6.8 after 0.5 h 10-30%, in particular 10-20%, after2 h 40-60%, in particular 40-50%, and after 6 h at least 80%, inparticular at least 85%.

The pellet formulations according to the invention can be preparedaccording to conventional processes known to the person skilled in theart. For example, the matrix material is first mixed with the activecompound and, if appropriate, the further pharmaceutically tolerableadditives and shaped to give pellets. The coating is then applied, e.g.sprayed on, in the form of a lacquer suspension in a suitable suspendingagent such as ethanol and/or water. The pellets can in this case have asize of 0.1-3 mm, preferably 0.5-1 mm, and are combined in unit doseforms such as tablets or capsules for the production of a medicament.The present invention therefore also relates to pharmaceuticalformulations which comprise the pellets according to the invention, inparticular gelatin capsules which contain the pellets according to theinvention.

On oral administration, the pellet formulations thus obtained result, incomparison with other preparations with the same active compound, inlower active compound concentrations in the blood with a simultaneouslyhigher concentration of the active compounds in the intestine, as aresult of which the side effect potential caused by the systemicallyavailable active compound or its metabolites, is markedly reduced.

The pellet formulation according to the invention is thus particularlysuitable for the treatment of intestinal conditions in which arelatively long-term administration of the active compound is indicated,such as inflammatory intestinal disorders in their active phase andtheir remission phase, in the prevention of adenomas and/or polypformation, in the prevention of the recurrence of adenomas and/or polypsand in the prevention of secondary disorders resulting therefrom andpossible accompanying disorders.

FIGS. 1 and 2 show graphs of the plasma concentrations of 5-ASA (FIG. 1)and Ac-5-ASA (FIG. 2) against time.

The following examples serve to illustrate the invention.

Example 1 describes two different pellet cores (Example 1.1-1.2) andfour different pellet coatings (Example 1.a-1.d). The different corescan be combined in any desired manner with the different coatings, thepellet core from Example 1.1 together with the coating from Example 1.abeing a particularly preferred example.

EXAMPLE 1

Examples of pellet cores:

1.1

I Mesalazine 5000 g II Cellulose, microcrystalline 1500 g IIIHydroxypropylmethylcellulose 200 g IV Silica 25 g V Poly(ethyl acrylate,methyl 750 g methacrylate) 2:1 as a 40% strength aqueous dispersion,tradename Eudragit ® NE 40 D VI Magnesium stearate 250 g

I-IV are mixed, moistened with V and intensively kneaded. VI is finallyscattered in. The moist mass is pressed through an extruder with a diebore of 1 mm. The extruded pellets are cut into pieces about 1 mm longand rounded in a spheronizer. The pellets are dried at 60° C.

1.2

I Mesalazine 5000 g II Cellulose, microcrystalline 1500 g IIIHydroxypropylmethylcellulose 200 g IV Silica 25 g V Poly(ethyl acrylate,methyl 2500 g methacrylate, trimethylammonioethyl methacrylate chloride)1:2:0.1; as a 12.5% strength isopropanolic solution; tradenameEudragit ® RS 12.5 VI Magnesium stearate 250 g

I-IV are mixed, moistened with V and intensively kneaded. VI is finallyscattered in. The moist mass is pressed through an extruder with a diebore of 1 mm. The extruded pellets are cut into pieces about 1 mm longand rounded in a spheronizer. The pellets are dried at 60° C.

Examples of Pellet Coatings

Formulations for 5000 g pellets, corresponding to Examples 1.1-1.2

1.a

I Poly(methacrylic acid, methyl 750 g methacrylate) 1:1; tradenameEudragit ® L 100; (methacrylic acid copolymer, USP/NF type A) IITriethyl citrate 75 g III Talc 200 g IV Titanium dioxide 125 g VMagnesium stearate 50 g

I is dissolved in 7000 g of an ethanol/water mixture (8:2). II-V aresuspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

1.b

I Poly(methacrylic acid, methyl 350 g methacrylate) 1:2; tradenameEudragit ® S; (methacrylic acid copolymer, USP/NF type B) II Triethylcitrate 35 g III Talc 100 g IV Titanium dioxide 125 g V Magnesiumstearate 50 g

I is dissolved in 3500 g of an ethanol/water mixture (8:2). II-V aresuspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

1.c

I Poly(methacrylic acid, methyl 420 g methacrylate) 1:2; tradenameEudragit ® S; (methacrylic acid copolymer, USP/NF type B);poly(methacrylic acid, methyl methacrylate) 1:1; tradename Eudragit ® L100; (methacrylic acid copolymer, USP/NF type A) (mixed in the ratio1.1:1) II Triethyl citrate 75 g III Talc 200 g IV Titanium dioxide 125 gV Magnesium stearate 50 g

I is dissolved in 5000 g of an ethanol/water mixture (8:2). II-V aresuspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

1.d

I Methylhydroxypropylcellulose 410 g phthalate II Ethylcellulose 44 gIII Polyethylene glycol 6000 40 g IV Talc 200 g V Titanium dioxide 125 gVI Magnesium stearate 50 g

I and II are dissolved in 5000 g of an ethanol/water mixture (9:1).III-VI are suspended in the solution; the lacquer suspension is sprayedon at a feed air temperature of 40° C. in a suitable apparatus.

EXAMPLE 2

To determine the release of the active compound from the pelletsaccording to the invention, the “basket” method was used. The stirrerspeed was 100 rpm and the temperature was kept constant at 37° C. 0.1 MHCl according to USP was used as artificial gastric juice and USPphosphate buffer (pH 6.8) as artificial intestinal juice.

Table 1 indicates the active compound release of the pellet formulationaccording to the invention having a core according to Example 1.1 and acoating according to Example 1.a under the abovementioned conditions.

TABLE 1 Release pH Time [min] [%] 1.2 120 1.6 6.8  30 12.2  60 24.9  9036.0 120 45.2 150 53.0 180 59.7 240 70.6 300 78.8 360 85.4

EXAMPLE 3

In order to obtain results about the active compound absorption into theblood after administration of the pellet formulation according to theinvention, the plasma concentrations of 5-ASA and acetyl-5-ASA(Ac-5-ASA), its degradation product, were investigated in atime-dependent manner. In a cross-over arrangement, 24 healthy subjectsreceived 500 mg of 5-ASA in two different pharmaceutical formulations(pellets according to the invention having a core according to Example1.1 and coating according to Example 1.a and commercially availableSalofalk® tablets (mesalazine in the form of enteric tablets) as acomparison preparation) over a period of 4 days (3×500 mg of 5-ASAdaily). To determine the plasma concentration of 5-ASA and acetyl-5-ASA,venous blood samples were taken from the subjects.

Tab. 2 shows the plasma concentration of 5-ASA and Ac-5-ASA averagedfrom 24 patients under steady-state conditions.

TABLE 2 Plasma concentration of 5-ASA and Ac-5-ASA in 24 subjects[ng/ml] (mean value) Time after Comparison administration Pelletspreparation [h] [5-ASA] [Ac-5-ASA] [5-ASA] [Ac-5-ASA] 0 63.49 676.35198.42 1033.89 1 71.50 739.46 96.66 711.70 2 102.97 731.34 82.86 657.163 382.02 1063.59 156.55 675.83 4 686.03 1549.00 1293.30 1651.01 5 527.391653.73 1564.33 2511.99 6 456.70 1493.00 924.75 2243.11 7 384.25 1442.96492.91 1755.05 8 257.16 1196.51 275.11 1377.46

It is evident from Table 2 and from FIGS. 1 and 2 that markedly lowerplasma levels can be achieved both from 5-ASA and from its metaboliteAc-5-ASA if 5-ASA is administered to the subjects in the form of thepellet formulation according to the invention. This result is confirmedby the average C_(max) values (average of the C_(max) values calculatedfrom the data of the individual subjects). In the case of the comparisonformulation, the average C_(max) value was 2001 ng/ml for 5-ASA and 2617ng/ml for Ac-5-ASA while in the case of the pellet formulation accordingto the invention the average C_(max) value was 755 ng/ml for 5-ASA and1810 ng/ml for Ac-5-ASA. The average C_(max) value of the pelletformulation is thus only 37.7% of the average C_(max) value of thecomparison formulation for 5-ASA and only 69% for Ac-5-ASA.

EXAMPLE 4

In order to confirm an increased local release of the 5-ASA in theintestine, feces samples of 4 subjects who had received 1500 mg of 5-ASAwere investigated for 5-ASA and Ac-5-ASA in a further investigation. Tothis end, the feces of the subjects were collected for 71 hours andinvestigated for free 5-ASA and Ac-5-ASA which were not bound in thepellet or in the comparison formulation (Tab. 3). The pellets accordingto the invention employed were those having a core according to Example1.1 and a coating according to Example 1.a; the comparison preparationused was commercially available Salofalk® tablets (mesalazine in theform of enteric tablets).

TABLE 3 Cumulative fecal excretion of 5-ASA and 5-Ac-ASA of 4 subjects[mg] (mean value) Pellets Comparison preparation [5-ASA] [Ac-S-ASA][5-ASA] [Ac-5-ASA] 287.5 367.9 222.9 275.7

It is evident from the table that both the amount of the 5-ASA releasedin the intestine by the pellet formulation according to the invention,at 287.5 mg, and the amount of free Ac-5-ASA, at 367.9 mg, is higher by29% or 44% respectively than in the comparison formulation. SinceAc-5-ASA can only be formed in the intestine by the interaction with theintestinal mucous membrane, the increased amount of Ac-5-ASA in thepellet formulation shows that markedly more active compound comes intocontact with the intestinal mucous membrane and can thus display itscurative action than in the comparison formulation.

These investigations confirm that the concentration of the activecompound 5-ASA or its degradation product Ac-5-ASA in the blood can besignificantly lowered by the pellet formulation according to theinvention in comparison with commercially available 5-ASA preparationsand thus the danger of possible side effects (nephrotoxicity etc.) isalso lower. As a result of the reduced absorption of the active compoundinto the blood, markedly higher amounts of the active compound areavailable in the intestine. These also come into contact with theintestinal mucous membrane and can display their action there, as theamounts of Ac-5-ASA, which are higher in comparison with the comparisonformulation and which are formed in the intestine by the direct contactof 5-ASA with the intestinal mucous membrane, confirm. Unlike thesystemically available 5-ASA and Ac-5-ASA, the 5-ASA and Ac-5-ASApresent in the intestine cannot have a nephrotoxic action, since it isnot excreted via the kidney, but with the feces.

Thus the pellet formulation according to the invention is preferablysuitable for intestinal conditions in which a relatively long-termadministration of the active compound is indicated, such as inflammatoryintestinal disorders in their active phase and in their remission phase,in the prevention of polyp formation, in the prevention of therecurrence of polyps and in the prevention of secondary disordersresulting therefrom and possible accompanying disorders.

What is claimed is:
 1. An orally administrable pharmaceutical pellet formulation having a controlled release profile for the treatment of the intestinal tract, which comprises a core and an enteric coating, the core including, as a pharmaceutically active compound, 5-aminosalicylic acid, or a pharmaceutically tolerable salt thereof, homogeneously dispersed in a non gel-forming polymer matrix which extends through the entire core and which is essentially insoluble in the intestinal tract and permeable to intestinal fluids; wherein the matrix is a poly(ethyl acrylate, methyl methacrylate) 2:1 matrix; and wherein the matrix-forming polymer makes up at least 1% by weight of the total weight of the core; and wherein the enteric coating comprises poly(methacrylic acid, methyl methacrylates) 1:1 or 1:2; and wherein the release of said active compound in 0.1 M HCl after 2 hours is <10%; the release of said active compound in artificial gastric juice at pH=6.8 after 0.5 hours is 10-30%, after 2 hours is 40-60% and after 6 hours is at least 80%. 